Insufficient vitamin D, as assessed by low circulating 25-hydroxyvitamin D [25(OH)D], has recently drawn attention as a potential cardiovascular disease (CVD) risk factor. However, much remains unknown about the relation of vitamin D to specific CVD events, and the impact of low vitamin D levels in the African-American population. African-Americans are particularly prone to hypovitaminosis-D due to reduced 25(OH)D synthesis as a consequence of greater cutaneous melanin content. Given that approximately 40%-60% of the general population has suboptimal vitamin D levels, which are amenable to correction through increased sunlight exposure and/or dietary supplementation, elucidating the role of vitamin D in CVD risk is of vital public health importance. Further, it is unclear whether levels of parathyroid hormone (PTH) or fibroblast growth factor-23 (FGF23), biomarkers closely linked to 25(OH)D, also influence CVD risk. In order to address key research questions about the relation of 25(OH)D, PTH, and FGF23 to specific CVD outcomes, we propose to measure these biomarkers in stored serum from visit 2 (1990-1992) of the prospective, population-based Atherosclerosis Risk in Communities (ARIC) cohort, which has followed 15,792 African-American (27%) and white (73%) participants for 20 years. We will then evaluate whether levels of 25(OH)D, PTH, and FGF23 are related to risk of incident coronary heart disease, stroke, atrial fibrillation, congestive heart failure, and peripheral artery disease. We will also evaluate whether these biomarkers are related to CVD risk factors, including diabetes and hypertension. Further, we will report race-stratified associations, and explore whether there are race-interactions present in the relation of these biomarkers to CVD risk factors and events. In exploratory analyses, we will also assess the relation of vitamin D receptor (VDR) gene polymorphisms to CVD risk, and evaluate whether relations of 25(OH)D to CVD are modified by VDR gene polymorphisms. Lastly, in order to identify genetic determinants of 25(OH)D levels, we propose to conduct genome wide association studies (GWASs) of 25(OH)D among ARIC Caucasians and African-Americans. This study will, in a biethnic population, provide some of the first information on the relation of 25(OH)D, PTH, and FGF23 to incidence of numerous CVD phenotypes, allow for exploration of the relative contributions of these biomarkers to CVD risk, and enhance understanding of the genetic influences on vitamin D. Given the pervasiveness of vitamin D insufficiency, and its potential for cost-effective correction through increased sunlight exposure and/or dietary supplementation, the findings of this study may have major implications for cardiovascular disease prevention. PUBLIC HEALTH RELEVANCE: A large proportion of the population (40-60%) has low levels of vitamin D, which may increase the risk of cardiovascular disease. This research aims to clarify the relation of vitamin D to cardiovascular disease. Given that it is possible to correct low vitamin D levels through increased sunlight exposure and/or dietary supplementation, the findings of this study may have major implications for cardiovascular disease prevention.